CD44 variant-dependent regulation of redox balance in EGFR mutation-positive non-small cell lung cancer: A target for treatment

被引：8

作者：

Kawano, Yuko ^{[1
]}

Iwama, Eiji ^{[1
]}

Tsuchihashi, Kenji ^{[2
]}

Shibahara, Daisuke ^{[1
]}

Harada, Taishi ^{[1
]}

Tanaka, Kentaro ^{[1
]}

Nagano, Osamu ^{[3
]}

Saya, Hideyuki ^{[3
]}

Nakanishi, Yoichi ^{[1
]}

Okamoto, Isamu ^{[1
]}

机构：

[1] Kyushu Univ, Grad Sch Med Sci, Res Inst Dis Chest, Higashi Ku, 3-1-1 Maidashi, Fukuoka 8128582, Japan

[2] Kyushu Univ, Grad Sch Med Sci, Dept Med & Biosyst Sci, Higashi Ku, 3-1-1 Maidashi, Fukuoka 8128582, Japan

[3] Keio Univ, Sch Med, Inst Adv Med Res, Div Gene Regulat,Shinjuku Ku, 35 Shinano Machi, Tokyo 1608582, Japan

来源：

LUNG CANCER | 2017年 / 113卷

基金：

日本学术振兴会;

关键词：

CD44 variant (CD44v); Reactive oxygen species (ROS); Epidermal growth factor receptor (EGFR); Non-small cell lung cancer (NSCLC); Glutathione; Chemosensitization; EPIDERMAL-GROWTH-FACTOR; SMALL G-PROTEINS; FACTOR RECEPTOR; BUTHIONINE SULFOXIMINE; OXIDATIVE STRESS; SYSTEM XC(-); TUMOR-CELLS; RHO FAMILY; PHASE-I; CLEAVAGE;

D O I：

10.1016/j.lungcan.2017.09.008

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Objectives: The regulation of redox balance in cancer cells is an important factor in tumor development and chemoresistance, with oncogene activation having been shown to induce the generation of reactive oxygen species (ROS). Activating mutations of the epidermal growth factor receptor gene (EGFK) are oncogenic drivers in non-small cell lung cancer (NSCLC), but it has remained unknown whether ligand-independent EGFR signaling conferred by EGFR mutation triggers ROS generation in NSCLC cells. Materials and Methods: HEK293T cells were transfected with an expression vector for mutant EGFR. The expression of CD44 variant (CD44v) isoforms in NSCLC cell lines was evaluated by flow cytometry. Cells were depleted of CD44v by RNA interference and assayed for ROS and glutathione (GSH) levels. The effect of CD44v on cisplatin sensitivity was evaluated in vitro with the MTS assay. Results: EGFR signaling due to EGFR mutation increased ROS levels in transfected HEK293T cells. The expression of CD44v isoforms was found to be inversely correlated with basal ROS levels in EGFR mutation-positive NSCLC cell lines. Knockdown of CD44v induced depletion of intracellular GSH and increased ROS levels in EGFR-mutated NSCLC cells that express CD44v at a high level (CD44v(high)). In addition, depletion of GSH by treatment with buthionine-[S, R]-sulfoximine induced marked accumulation of ROS and enhanced the cytotoxicity of cisplatin in CD44v(high) EGFR-mutated NSCLC cells but not in corresponding CD44v(low) cells. This enhancement of cisplatin cytotoxicity by GSH depletion was prevented by treatment with the antioxidant N-acetyl-L-cysteine. Knockdown of CD44v also enhanced cisplatin cytotoxicity in CD44v(hlgh) EGFR mutation-positive NSCLC cells but not in CD44v(low) cells. Conclusion: Our results thus implicate CD44v in redox adaptation and as a potential target for treatment in CD44v(high) EGFR-mutated NSCLC cells.

引用

页码：72 / 78

页数：7

共 43 条

[1]

Azad MB, 2009, ANTIOXID REDOX SIGN, V11, P777, DOI [10.1089/ars.2008.2270, 10.1089/ARS.2008.2270]

[2]

Bae Y. S., 1997, J BIOL CHEM, V272

[3] Phase I study of continuous-infusion L-S,R-buthionine sulfoximine with intravenous melphalan [J].